EJP18 peptide derived from the juxtamembrane domain of epidermal growth factor receptor represents a novel membrane-active cell-penetrating peptide

Eissa, Noura G.; Sayers, Edward J.; Birch, Ditlev; Patel, Sanjay G.; Tsai, Yu‐Hsuan; Nielsen, Hanne Mørck; Jones, Arwyn Tomos

doi:10.1042/bcj20190452

Cited by 8 publications

(3 citation statements)

References 58 publications

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“…In addition, no animal exhibited obvious changes in physical appearance, activity level, or body weight. Although no signs of toxicity were observed in the present study, previous studies have suggested that CPPs might act as double edge swords mediating a wide variety of unpredictable biological effects 38 , 57 – 59 . For this reason, we cannot fully rule out potential toxicity despite the high doses used in this study.…”

Section: Discussioncontrasting

confidence: 87%

Pharmacokinetics, biodistribution and toxicology of novel cell-penetrating peptides

Reveret

Leclerc

Morin

et al. 2023

Sci Rep

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Cell-penetrating peptides (CPPs) have been used in basic and preclinical research in the past 30 years to facilitate drug delivery into target cells. However, translation toward the clinic has not been successful so far. Here, we studied the pharmacokinetic (PK) and biodistribution profiles of Shuttle cell-penetrating peptides (S-CPP) in rodents, combined or not with an immunoglobulin G (IgG) cargo. We compared two enantiomers of S-CPP that contain both a protein transduction domain and an endosomal escape domain, with previously shown capacity for cytoplasmic delivery. The plasma concentration versus time curve of both radiolabelled S-CPPs required a two-compartment PK analytical model, which showed a fast distribution phase (t1/2α ranging from 1.25 to 3 min) followed by a slower elimination phase (t1/2β ranging from 5 to 15 h) after intravenous injection. Cargo IgG combined to S-CPPs displayed longer elimination half-life, of up to 25 h. The fast decrease in plasma concentration of S-CPPs was associated with an accumulation in target organs assessed at 1 and 5 h post-injection, particularly in the liver. In addition, in situ cerebral perfusion (ISCP) of L-S-CPP yielded a brain uptake coefficient of 7.2 ± 1.1 µl g−1 s−1, consistent with penetration across the blood–brain barrier (BBB), without damaging its integrity in vivo. No sign of peripheral toxicity was detected either by examining hematologic and biochemical blood parameters, or by measuring cytokine levels in plasma. In conclusion, S-CPPs are promising non-toxic transport vectors for improved tissue distribution of drug cargos in vivo.

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Section: Discussioncontrasting

confidence: 87%

Pharmacokinetics, biodistribution and toxicology of novel cell-penetrating peptides

Reveret

Leclerc

Morin

et al. 2023

Sci Rep

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“…By modifying the sequence of natural CPPs, semi-synthetic CPPs have also been produced. While the cell penetrating potential of CPPs was originally assumed to be a peculiar property, a large number of peptide sequences, with confirmed and putative membrane penetration capability have been identified in human proteins as well [ 6 ]. Furthermore, novel, purely synthetic, or partially natural chimeric peptides were also constructed.…”

Section: Introductionmentioning

confidence: 99%

Effect of the Lipid Landscape on the Efficacy of Cell-Penetrating Peptides

Zakany

Mándity

Varga

et al. 2023

Cells

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Every cell biological textbook teaches us that the main role of the plasma membrane is to separate cells from their neighborhood to allow for a controlled composition of the intracellular space. The mostly hydrophobic nature of the cell membrane presents an impenetrable barrier for most hydrophilic molecules larger than 1 kDa. On the other hand, cell-penetrating peptides (CPPs) are capable of traversing this barrier without compromising membrane integrity, and they can do so on their own or coupled to cargos. Coupling biologically and medically relevant cargos to CPPs holds great promise of delivering membrane-impermeable drugs into cells. If the cargo is able to interact with certain cell types, uptake of the CPP–drug complex can be tailored to be cell-type-specific. Besides outlining the major membrane penetration pathways of CPPs, this review is aimed at deciphering how properties of the membrane influence the uptake mechanisms of CPPs. By summarizing an extensive body of experimental evidence, we argue that a more ordered, less flexible membrane structure, often present in the very diseases planned to be treated with CPPs, decreases their cellular uptake. These correlations are not only relevant for understanding the cellular biology of CPPs, but also for rationally improving their value in translational or clinical applications.

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“…Small molecule allosteric inhibitors such as EAI045 and JBJ-04-125-02 inhibit the kinase activity of oncogenic EGFR variants (most notably L858R/T790M/C797S EGFR) by binding to an allosteric pocket located within the kinase domain. In addition, there are now several reports − of peptide or peptidomimetic inhibitors that target the JM segment, an intracellular region whose dimerization is essential for kinase activation. − One set of inhibitors consists of cell-permeant hydrocarbon-stapled peptides − designed to inhibit EGFR by blocking the formation of the antiparallel JM coiled coil dimer within the receptor cytoslic domain (Figure ). , …”

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confidence: 99%

Allosteric Inhibition of the Epidermal Growth Factor Receptor

et al. 2021

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We previously reported a family of hydrocarbon-stapled peptides designed to interact with the epidermal growth factor receptor (EGFR) juxtamembrane (JM) segment, blocking its ability to form a coiled coil dimer that is essential for receptor activation. These hydrocarbon-stapled peptides, most notably E1S, decreased the proliferation of cell lines that express wild-type EGFR (H2030 and A431) as well as those expressing the oncogenic mutants EGFR L858R (H3255) and L858R/T790M (H1975). Although our previous investigations provided evidence that E1S interacted with EGFR directly, the location and details of these interactions were not established. Here we apply biochemical and cross-linking mass spectrometry tools to better define the interactions between E1S and EGFR. Taken with previously reported structure–activity relationships, our results support a model in which E1S interacts simultaneously with both the JM and the C-lobe of the activator kinase, effectively displacing the JM of the receiver kinase. Our results also reveal potential interactions between E1S and the N-terminal region of the C-terminal tail. We propose a model in which E1S inhibits EGFR by both mimicking and inhibiting JM coiled coil formation. This model could be used to design novel, allosteric (and perhaps nonpeptidic) EGFR inhibitors.

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EJP18 peptide derived from the juxtamembrane domain of epidermal growth factor receptor represents a novel membrane-active cell-penetrating peptide

Cited by 8 publications

References 58 publications

Pharmacokinetics, biodistribution and toxicology of novel cell-penetrating peptides

Pharmacokinetics, biodistribution and toxicology of novel cell-penetrating peptides

Effect of the Lipid Landscape on the Efficacy of Cell-Penetrating Peptides

Allosteric Inhibition of the Epidermal Growth Factor Receptor

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